In Vitro Glucuronidation of Fenofibric Acid by Human UDP-Glucuronosyltransferases and Liver Microsomes

Tojcic, Jelena; Benoit‐Biancamano, Marie‐Odile; Court, Michael H.; Straka, Robert J.; Caron, Patrick; Guillemette, Chantal

doi:10.1124/dmd.109.029058

Cited by 17 publications

(14 citation statements)

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“…UGT2B7 is an enzyme responsible for detoxification of xenobiotics, including drugs such as morphine, efavirenz, zidovudine, and fenofibric acid, and is involved in the homeostasis of endogenous molecules like eicosanoids, bile acids, and sex steroids (Jin et al, 1997;Barbier et al, 2000;Stone et al, 2003;Turgeon et al, 2003;Thibaudeau et al, 2006;Mano et al, 2007;Bélanger et al, 2009;Tojcic et al, 2009;Trottier et al, 2013). Its expression is high in liver and kidney, but is also detectable in the gastrointestinal tract and peripheral tissues (Nakamura et al, 2008;Court et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

et al. 2013

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The enzyme UGT2B7 is one of the most active UDP-glucuronosyltransferases (UGTs) involved in drug metabolism and in maintaining homeostasis of endogenous compounds. We recently reported the existence of 22 UGT2B7 mRNAs, two with a classic 59 region but alternative 39 ends namely UGT2B7_v5 (containing a novel terminal exon 6b) and _v7 (exon 5 excluded) that encode enzymatically inactive isoforms 2 and 4 (i2 and i4), respectively. The v1 mRNA encoding the UGT2B7 enzyme (renamed isoform 1 or i1) is coexpressed with the splice variants v5 and v7 in human liver, kidney, and small intestine and the hepatic cell lines HepG2 and C3A. The presence of alternate v5 and v7 transcripts in isolated polysomes from these hepatic cells further supports endogenous protein translation. Cellular fractionation of clonal HEK293 cell lines overexpressing UGT2B7 isoforms demonstrates that i1, i2, and i4 proteins colocalize in the microsomal/Golgi fraction, whereas i2 and i4 can also be found in the cytosol; a finding sustained by immunofluorescence experiments using tagged proteins. By modifying splice variant abundance in overexpression in HEK293 and HepG2 cells as well as RNA interference experiments in HepG2 and C3A cells, we observe drug glucuronidation phenotypes compatible with variant-mediated repression of UGT2B7 activity without consequent alteration of the apparent enzyme affinity (K m ). Finally, coimmunoprecipitation experiments support a direct proteinprotein interaction of i2 and i4 proteins with the functional UGT2B7 enzyme as a potential causative mechanism. These findings point toward a novel autoregulatory mechanism of the UGT2B7 glucuronidation pathway by naturally occurring alternative i2 and i4 proteins.

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Section: Introductionmentioning

confidence: 99%

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

et al. 2013

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“…Fenofibric acid is also metabolized in the liver by UGTs [46] mainly through UGT2B7 [47] and UGT1A9 [46] resulting in conjugation with glucuronic acid and subsequent excretion in urine with a half-life of 20 hours. Since UGT1A9 is a high affinity and low capacity enzyme implicated in both fenofibric acid [47] and MPA conjugation, competition between MPA and fenofibric may have been an additional mechanism leading to increased plasma concentrations of MPA (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Since UGT1A9 is a high affinity and low capacity enzyme implicated in both fenofibric acid [47] and MPA conjugation, competition between MPA and fenofibric may have been an additional mechanism leading to increased plasma concentrations of MPA (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

Severe Neutropenia in a Renal Transplant Patient Suggesting an Interaction Between Mycophenolate and Fenofibrate

Álvarez¹,

Egozcue²,

Sleiman³

et al. 2012

CDS

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Objective: To describe a patient in whom initiation of micronized fenofibrate precipitated mycophenolate induced neutropenia.Case Summary: A 57-year-old man was admitted to the hospital because of febrile neutropenia. He had undergone kidney transplantation seventeen years ago. The patient's immunosuppressive maintenance regimen consisted of mycophenolate mofetil (MMF) 500 mg three times a day, and meprednisone 4 mg daily. His medical history included, hypertension treated with losartan 50mg daily, and dyslipidemia treated with ezetimibe 10mg /simvastatin 20mg for four years (until 2 weeks before admission when micronized fenofibrate 200 mg per day was started because of persistently elevated triglycerides levels. On presentation temperature was 37.8ºC and initial laboratory tests showed 3130 White Blood Cell Count(WBC)/μL with neutropenia (absolute neutrophil count (ANC) 313/μL) Fenofibrate and mycophenolate mofetil were discontinued, piperacillin tazobactam 4.5gr three times a day and granulocyte stimulation factor 300 μg/day were started. Three days after admission WBC was 7280/μL, neutrophils: 22%, ANC: 1160/mm 3 . Mycophenolate mofetil was restarted and granulocyte stimulation factor was discontinued. One month after discharge his WBC was 4480/μL and ANC 1926/μL. Discussion:The initiation of fenofibrate in a patient on stable and therapeutic doses of mycophenolate may have precipitated mycophenolate induced neutropenia, a well described, dose dependent phenomenon. Mycophenolic acid (MPA) displays a complex pharmacokinetic profile susceptible to potential significant interactions with fenofibrate. Since approximately 99% of MPA and fenofibrate bind to albumin, displacement may occur, leading to increased free MPA. Second competition of fenofibric acid for UGT1A9 an enzyme implicated in conjugation of MPA may have decreased its metabolism. The combination of these two effects may increase the risk of dose dependent neutropenia. Using the Interaction Probability Scale (DIPS), the interaction was designated as probable.Conclusions: Until further evidence is available, when fenofibrate is started in a renal transplant patient on mycophenolate careful monitoring should be considered to avoid potentially fatal complications.

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Section: Genetic Modifiers Of Hdl-c Response To Drug Treatmentmentioning

confidence: 99%

“…In the case of fenofibrate, the elimination of fenofibric acid—the active moiety of the drug—occurs primarily through the glucuronidation pathway [43]. Assuming that access to the PPAR[alpha] site of action is indeed determined in part by circulating levels of fenofibric acid, as in vitro evidence suggests [43], genetic variation in uridine 5′-diphospho-glucuronosyltransferases emerges as a potentially important predictor of lipid response to fenofibrate. Data from the GOLDN study [44] have pursued associations between glucuronidation activity and fenofibrate response and established that uridine 5′-diphospho-glucuronosyltransferases are indeed important determinants of lipid changes, identifying a new class of markers that independently or in concert with other genes could eventually be used to predict HDL-C response to fenofibrate therapy.…”

Section: Genetic Modifiers Of Hdl-c Response To Drug Treatmentmentioning

confidence: 99%

Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

Aslibekyan¹,

Straka

Irvin

et al. 2013

Expert Review of Cardiovascular Therapy

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High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 genes have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts.

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In Vitro Glucuronidation of Fenofibric Acid by Human UDP-Glucuronosyltransferases and Liver Microsomes

Cited by 17 publications

References 40 publications

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

Modulation of the UGT2B7 Enzyme Activity by C-Terminally Truncated Proteins Derived from Alternative Splicing

Severe Neutropenia in a Renal Transplant Patient Suggesting an Interaction Between Mycophenolate and Fenofibrate

Pharmacogenomics of high-density lipoprotein-cholesterol-raising therapies

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